The DAP Kinases are serine/threonine kinases implicated in cell death. Mice deficient in a member of this family, Drak2, were produced by gene targeting and analyzed for lymphoid subsets and immune reactivity. Contrary to studies carried out using ectopic overexpression, no defect in activation induced cell death was noted in T lymphocytes or their progenitors. Instead, T cells from Drak2 -/- mice exhibit an autonomous hypersensitivity that renders them relatively independent of a requirement for CD28-mediated costimulation. Experiments are proposed to investigate the effect this co-stimulation independence has on induction and regulation of immunity. In addition, the signaling pathway regulated by DRAK2 will be investigated. Preliminary evidence indicates that it regulates the calcium-calcineurin activation pathway, and experiments will test this hypothesis by looking for biochemical interactions, and the dose-dependent regulation of NFAT activation. More generally, experiments are proposed to investigate the substrates of DRAK2 and the upstream mediators that affect DRAK2 activity. These experiments will elucidate a novel mechanism of immune regulation. The identification of a kinase that regulates the sensitivity of T cell activation constitutes in an important step in identifying therapeutics to regulate autoimmunity, immune responses to infectious agents, and tumor immunity.